A Robust and Cost‐Efficient Scheme for Accurate Conformational Energies of Organic Molecules

Abstract

Several standard semiempirical methods as well as the MMFF94 force field approximation have been tested in reproducing 8 DLPNO‐CCSD(T)/cc‐pVTZ level conformational energies and spatial structures for 37 organic molecules representing pharmaceuticals, drugs, catalysts, synthetic precursors, industry‐related chemicals (37conf8 database). All contemporary semiempirical methods surpass their standard counterparts resulting in more reliable conformational energies and spatial structures, even though at significantly higher computational costs. However, even these methods show unexpected failures in reproducing energy differences between several conformers of the crown ether 1,4,7,10,13,16‐hexaoxacyclooctadecane (18‐crown‐6). Inexpensive force field MMFF94 approximation groups with contemporary semiempirical methods in reproducing the correct order of conformational energies and spatial structures, although the performance in predicting absolute conformational energies compares to standard semiempirical methods. Based on these findings, we suggest a two‐step strategy for reliable yet feasible conformational search and sampling in realistic‐size flexible organic molecules: i) geometry optimization/preselection of relevant conformers using the MMFF94 force field; ii) single‐point energy evaluations using a contemporary semiempirical method. We expect that developed database 37conf8 is going to be useful for development of semiempirical methods.

Assessing Conformer Energies using Electronic Structure and Machine Learning Methods

“…45,65,66 Since some molecules in the original test set included iodine and some DLPNO-CCSD(T) By considering a large number of diverse organic molecules with many poses per molecule, we seek to sample a wide variety of conformer energy preferences (e.g., intramolecular hydrogen and halogen bonding, -stacking, electrostatic interactions, etc.). While using optimized low-energy conformers may under-estimate the accuracy of methods for high-energy struc-tures, 7 we believe the current work is a challenging but useful comparison. In general, such high-energy geometries reflect steric repulsion more than the diverse types of interactions driving low-energy geometries.…”

“…Previous work have suggested that the low correlations found between force field and semiempirical methods are derived from the small number of low-energy conformers considered in this benchmark. 7 Certainly, one might imagine that when considering multiple geometries with only small differences in energies, random errors are magnified. Figure 5 illustrates Despite the small ranges in energies, there is little correlation between the energy range of a molecule and the accuracy metrics of a particular method.…”

“…5 Multiple efforts have evaluated the success of wavefunction and density functional first principles methods to compare the energetics of different conformers. [6][7][8][9][10][11][12] While experimental crystal structures and bioactive docked conformers are not always the lowest energy conformer, recent efforts have demonstrated only small energy differences when using quantum chemical methods instead of force fields. 13,14 Even for simple molecules such as 1,1'-biphenyl, use of large basis set coupled cluster methods are needed to accurately place the dihedral angle and barrier.…”

Understanding the solubilization of Ca acetylide with a new computational model for ionic pairs

“…Conformational sampling with fast semi-empirical methods has seen tremendous development recently. [57][58][59][60] Combining them with DFT post-treatment allows, e.g., estimation of realistic IR spectra in solution 61 and reliable exhaustive conformational sampling of organic macrocycles. 62 Given the importance of CaC 2 as a sustainable carbon source for organic synthesis and Ca acetylides as potent intermediates, we performed this computational study.…”

Assessing Conformer Energies using Electronic Structure and Machine Learning Methods

“…[5] Multiple efforts have evaluated the success of wavefunction and density functional first-principles methods to compare the energetics of different conformers. [6], [7], [8], [9], [10], [11], [12] While experimental crystal structures and bioactive docked conformers are not always the lowest energy conformer, recent efforts have demonstrated only small energy differences when using quantum chemical methods instead of force fields. [13], [14] Even for simple molecules such as 1,1'-biphenyl, use of large basis set coupled cluster methods are needed to accurately place the dihedral angle and barrier.…”